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ARTICLE IN BRIEF

Investigators reported on behalf of the Alzheimer's Disease Cooperative Study group that there is enough of a signal to support continued development of solanezumab and other amyloid plaque-targeted biologics for the treatment of patients with mild, and perhaps even moderate Alzheimer's disease.

BOSTON —The experimental anti-beta amyloid monoclonal antibody solanezumab modestly slowed the progression of cognitive decline in patients with mild to moderate Alzheimer disease, according to a new report from the Alzheimer's Disease Cooperative Study (ADCS).

Patients with mild disease gained the most benefit — with cognitive decline slowing by almost one-third and even a hint of functional gain, Rachelle S. Doody, MD, PhD, professor of neurology and the Effie Marie Cain chair in Alzheimer's disease research at Baylor College of Medicine in Houston, reported on behalf of ADCS.

But when looked at as a separate subgroup, patients with moderate disease did not improve on any clinical outcome, according to the report, which took center stage here at the annual meeting of the American Neurological Association (ANA) last month.

While not the home run everyone had hoped for, many — but not all — Alzheimer's disease experts told Neurology Today that combined with a new biomarker analysis of bapineuzumab data — in which Pittsburgh compound-B PET scans revealed reduced accumulation of amyloid burden in patients taking bapineuzumab compared with those taking placebo — there is enough of a signal to support continued development of solanezumab and other amyloid plaque-targeted biologics for the treatment of patients with mild, and perhaps even moderate, disease.

SOLANEZUMAB MECHANISM

Solanezumab is a humanized monoclonal antibody that targets and binds to the mid region of amyloid beta, promoting its clearance from the brain.

Eli Lilly and Company, the drug's sponsor, announced in August 2012 that two phase 3 trials of solanezumab — EXPEDITION-1, involving 1,012 patients, and EXPEDITION-2, including 1,040 patients — failed, both missing their co-primary endpoints, a combination of cognitive and functional measures of daily living activities.

The company made the raw data from the two double-blind, placebo-controlled trials available to the ADCS. At ANA, those additional analyses were presented.

Among the findings of Lilly's original analysis of EXPEDITION-1, there was a statistically significant (p = 0.008) 42 percent reduction in cognitive decline at 18 months in patients with mild AD. But there was no statistically significant change in the functional measure of daily living activities.

In the EXPEDITION-2 trial, there was a non-significant 20 percent improvement in cognitive decline (p = 0.12) and a non-significant 19 percent improvement in functional decline (p = 0.076) in patients with mild AD.

Pooled data from the similarly designed trials showed that in patients with mild AD, solanezumab was associated with a significant 34 percent reduction in cognitive decline compared with placebo (p = 0.001). There was a 17 percent functional benefit in mild AD patients that did not reach significance (p = 0.057).

NEW ANALYSIS OF DATA: ADCS

The new ADCS analysis had generally similar results. In EXPEDITION-1, there was no significant difference between groups in the co-primary outcomes of cognitive decline (p =.12) or the functional measures (p =.84). And in EXPEDITION-2, there was no significant difference in the rates of cognitive decline in patients with mild AD (p =.08) or in functional decline in patients with mild or moderate AD (p =.12).

But when the mild and moderate patients were considered as a group by using the pooled data from both trials, solanezumab recipients had a significant 1.41-point lower score on cognitive measures (95% confidence interval, 0.35 - 2.47; p =.009) compared with those on placebo.

In both EXPEDITION-2 and in the pooled analysis, mild patients taking solanezumab did better on the functional measure of ADCS-ADL (both p = .04).

Solanezumab was generally well tolerated, with no adverse events in which the overall rate was greater than 2 percent and the rate in the combined arm was at least double the rate of the placebo arm.

The only side effect that affected 1 percent or more of patients that occurred more often in patients on solanezumab than in patients on placebo was angina: 1.1 percent vs. 0.2 percent.

STUDY PROTOCOLS

Patients in the trials were aged 55 to 94 years with mild to moderate AD, defined as 16 to 26 points on the 30-point Mini-Mental State Exam (MMSE) scale, in which lower scores indicate more dementia.

They received 400 mg of solanezumab or placebo by IV infusion every four weeks for 18 months. Patients could continue to take their other AD medications during the trials; most were taking an acetylcholinesterase inhibitor or memantine.

At baseline, there were no significant differences between the groups in either trial in terms of age, gender, apolipoprotein E4 status, education, or MMSE or ADASCog11 scores.

WHAT DO THE FINDINGS MEAN?

Experts offered mixed reviews of the data. Stephen Salloway, MD, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, RI, and professor of clinical neurosciences and psychiatry at Brown Medical School, said: “It is encouraging that there may be a positive clinical benefit. But I don't think we can say if it is enough for regulatory approval. It is quite clear the effect is modest, and people need to keep in mind that in a field where we have no disease-modifying treatments, this is a very encouraging finding….The evidence pointed to more effect in mild patients, and so future studies should focus on milder disease.” [Dr. Salloway is chair of the steering committee for the bapineuzumab trial.]

John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman distinguished professor of neurology at Washington University in St. Louis and director and principal investigator of the university's Alzheimer's Disease Research Center, said: “I think the encouraging signal is not just on cognition but on function, and that is what patients and families want — function to be improved or not get worse. If you get cognition, great, if you get function, that is even better.”

But physicians in the audience who heard the solanezumab and bapineuzumab presentations questioned whether “a 1.5-point change on ADAS-Cog” was adequate. “The acetylcholinesterase inhibitors [e.g., Pfizer's Aricept (donepezil)] have a bigger effect,” one neurologist in the audience commented, “and we have trouble keeping patients on those.”

Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, MN, told Neurology Today, “This is a modest effect, not a home run, in terms of clinical benefit.”

“I'm concerned that in mild to moderate disease, the clearance of plaque may not be effective because a lot of damage has already been done,” said Dr. Trojanowski, co-director of the Center for Neurodegenerative Disease Research; director of the Institute on Aging, and director of Alzheimer's Disease Core Center at Perelman School of Medicine at the University of Pennsylvania.

Dr. Trojanowski believes that the recent data points to a role of solanezumab for prevention of AD in high-risk persons, such as those who harbor a mutation known to raise risk. He noted that is one of three drugs being tested in the Dominantly Inherited Alzheimer's Network (DIAN) trial of mostly high-risk persons who do not yet show any signs of the disease. The other drugs to be tested are gantenerumab, made by Roche, which binds to amyloid, and another Lilly drug, LY2886721, which blocks the beta-secretase enzyme used to make amyloid.

“The question then comes up: What to do for the 5.5 million people [in the US] who already have Alzheimer's?” Dr. Trojanowski asked.

He is not the only expert that thinks it may be too late to intervene with anti-amyloid beta drugs once the disease is symptomatic.

DOUBTS ABOUT AMYLOID BETA HYPOTHESIS

With the failure of bapineuzumab and other experimental agents that inhibit amyloid beta production in recent trials, some have even expressed doubt about the amyloid hypothesis altogether. [See Neurology Today's “Bapineuzumab for Alzheimer's: Don't Write Off Negative Results Just Yet, Experts Say”: http://bit.ly/T8pDxI.] It maintains that amyloid-beta plaques that accumulate in the brain cause neurodegeneration and cognitive and functional decline.

Others are not dismissing anti-beta amyloid drugs for mild to moderate disease. “Amyloid is not the wrong target,” said Dr. Doody. “I think there are increasingly compelling genetic data to support the role of amyloid.”

Also, “I would take a little issue with a ‘once you have the disease, it is too late’ attitude…. If reducing the amyloid also reduces the tendency for tangles, that could be clinically impactful,” she said.

Still, earlier is better, all agreed.

“In heart disease, cancer, diabetes, osteoporosis — where we've had success — we have more success when we start earlier, but I do believe we should not give up on people with dementia,” said Reisa A. Sperling, MD, associate professor of neurology at Harvard Medical School and director of clinical research in the Memory Disorders Unit at Brigham and Women's Hospital in Boston. “I think if we started early enough, we would bend the curve.”

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